Drugs for treating viral infections

ABSTRACT

A series of substituted sulfonamide derivatives have been prepared and may be used to treat antiviral infections, especially infections caused by orthopoxviruses.

BACKGROUND OF THE INVENTION

[0001] The invention relates generally to carbocyclic imidodisulfamidederivatives and more specifically toN,N¹-bis[[tricyclo3.3.1.1^(3,7)]dec-1-yl]alkyl]-,N,N¹-bis[[tricyclo[3.3.1.1^(3,7)]dec-2-yl]alkyl]-, andN,N¹di(bicyclo[2.2.1]hept-2-yl)imidodisulfamide derivatives, as well astheir alkali salts and N-monophosphates. The compounds of this inventionpossess broad antiviral activity, especially activity againstorthopoxviruses.

[0002] Ali at al., J. Med. Chem. 25: 1235-1240 (1982) describe a seriesof N,N¹-bis(arylcyclopropyl)imidodisulfamide derivatives havingantiallergic activity. Appel and Helwerth, Chem. Ber. 101: 1743-1745(1968) disclose a bis(cyclohexyl)imidodisulfamide derivative. Yamaguchiand Nakano [Japan. Patent 19,962 (1963)] disclose the ammonium salt of abis(cyclohexyl)imidodisulfamide derivative.

SUMMARY OF THE INVENTION

[0003] In accordance with the invention, there are provided compounds ofthe formula:

[R—(CH₂)_(n)NHSO₂]₂NR¹   (I)

[0004] wherein n is 0, 1 or 2, R is a carbocyclic radical selected fromthe group consisting of adamantyl, norbornyl, cyclooctyl andcyclododecyl, and R¹ is hydrogen, alkali metal such as sodium,potassium, etc., ammonium cation, and monophosphate moiety.

[0005] The invention further provides a method for treating a warmblooded animal for viral infections, preferably but not limited toinfections caused by orthopoxviruses (such as vaccinia virus, cowpox,smallpox, monkeypox, camelpox, etc.) which method comprisesadministering to such animal an effective amount of a compound offormula (I).

DETAILED DESCRIPTION OF THE INVENTION

[0006] The compounds of the invention may be prepared by reacting anappropriate carbocyclic alkylamine derivative (1) with imidodisulfurylchloride (2) in the presence of triethylamine (n and R are as definedabove):

[0007] The following carbocyclic alkylamine intermediates (1) arecommercially available: tricyclo [3.3.1.1^(3,7)]decan-1-amine (1;PR=1-adamantyl, n=0); [(tricyclo[3.3.1.1^(3,7)]-dec-1-yl)methyl]amine(1; R=1-adamantylmethyl, n=1); tricyclo[3.3.1.1^(3,7)]decan-2-amine(1;R=2-adamantyl, n=0); exo-bicyclo [2.2.1heptan-2-amine (1;R=exo-2-norbornyl, n=-0); and endo-bicyclo[2.2.1]heptan-2-amine (1;R=endo-2-norbornyl, n=0).

[0008] Tricyclo[3.3.1.1^(3,7) ]decan-1-ethanamine (1; R=1-adamantyl,n=−2) may be prepared according to U.S. Pat. No. 3,534,036 of V. L.Narayanan and F. L. Weisenborn, the entire disclosure of which isincorporated herein by reference.

[0009] Tricyclo[3.3.1.1^(3,7)]decan-2-ethanamide (1; R=2-adamantyl, n=2)and 2-(tricyclo[3.3.1.13,7]dec-2-ylidene)ethanamine (4)

[0010] were prepared according to the procedure of Mariani et al., IlFarmaco, Ed. Sci. 31: 272 (1976) and Schenonone et al. Il Farmaco, Ed.Sci. 27: 322 (1972).

[0011] Imidodisulfuryl chloride was prepared utilizing the procedure ofAppel and Eisenhouer, Chem. Ber. 95: 1753 (1962).

[0012] The compounds of the invention may also be prepared as theirammonium salts (6) by reacting an appropriate carbocyclic alkylaminederivative (1) (n and R are defined as above) with the ammonium salt ofimidodisulfuryl chloride (5) according to the procedures of Appel andHelwerth [Chem. Ber. 101: 1743-1745 (1968)] and Yamaguchi and Nakano[Japan. Patent 19,962 (1963)]:

[0013] In order to increase their solubility in water and saline, thecompounds of the invention may also be prepared as their alkali salts(8) by reacting an appropriate carbocyclic imidodisulfamide derivative 3(n and R are defined as above) with aqueous alkaline hydroxide solutionsuch as but not limited to sodium hydroxide and potassium hydroxide:

[0014] In order to increase their solubility in water and saline, thecompounds of the invention may also be prepared as their N-substitutedmonophosphate derivatives (10) according to the procedure of Zavlin andEfremov, Phosphorous Sulfur, 40: 247-251 (1991) by reacting anappropriate carbocyclic imidodisulfamide derivative 3 (n and R aredefined as above) with a phosphorylating agent 9 (e.g., phosphoricanhydride, phosphorus trichloride, phosphorous pentoxide and phosphorousoxychloride):

[0015] By having increased solubility in water and saline, compounds ofthe formula 6, 8 and 10 may be easily administrated by oral, intranasal,and intraperitoneal routes to treat warm-blooded animals againstinfections caused by orthopoxviruses.

[0016] The present invention is illustrated in more detail by referenceto the following non-limiting examples.

EXAMPLE 1

[0017] N, Ni-Bis (tricyclo[3.3.1.1^(3,7)]dec-1-yl) imidodisulfamide (3;R=1-adamantyl, n=0)

[0018] Under a nitrogen atmosphere, triethylamine (177.71 mL, 1.275 mol)was added over 1.75 hour to a solution of imidodisulfuryl chloride(90.95 g, 0.425 mol) in 2.55 L of anhydrous acetonitrile at −40° C. (dryice/acetone bath). The resulting yellow solution was stirred at −40° C.for 1 hour and then allowed to warm to 0° C. While stirring rapidly,solid tricyclo[3.3.1.1^(3,7)]decan-1-amine (192.84 g, 1.275 mol) wasadded portionwise over 2 hours at such a rate that allowed thetemperature of the reaction mixture to be maintained at −5 to 0° C. for1 hour, and at room temperature for 18 hours, the insolubles werefiltered off and the filtrate evaporated under reduced pressure. Theresulting residue and the insolubles were combined and dissolved in 2 Lof methanol. The methanolic solution was acidified with 2 equivalents of2 N hydrochloric acid (490 L), and stirred at ambient temperature for 30min. After dilution with 2.5. L of water, a precipitate formed. Thereaction mixture was filtered off and the crude solid was recrystallizedfrom ethanol providing 105.4 g of white crystalline compound 3(R=1-adamantyl, n=0). M.p. 210° C. (decomp.). Anal. Calcd. ForC₂₀H₃₃N₃O₄S₂: C, 54.15; H, 7.50; N, 9.47; S, 14.45. Found: C, 54.00; H,7.52; N; 9.55; S, 14.54.

EXAMPLE 3

[0019] Exo-N,N¹-Bis(bicyclo[2.2.1]hept-2-yl)imidodisulfamide (3;R=2-norbornyl, n=0)

[0020] The compound of the example was prepared by a procedure similarto that described in Example 1 except thatexo-bicyclo[2.2.1]heptan-2-amine (1; R=exo-2-norbornyl, n=0) wassubstituted for tricyclo[3.3.1.1^(3,7)]-decan-1-amine. M.p. 208° C.(ethanol). Anal. Calcd. For C₁₄H₂₅N₃O₄S₂: C, 46.26; H, 6.93; N, 11.56;S, 17.64. Found: C, 46.22; H, 6.96; N, 11.51; S, 17.71.

EXAMPLE 3

[0021] Endo-N,N¹-Bis (bicyclo (2.2.1]hept-2-yl) imidodisulfamide (3;R=2-norbornyl, n=0)

[0022] The compound of this example was prepared by a procedure similarto that described in Example 1 except thatendo-bicyclo[2.2.1]heptan-2-amine (1; R=endo-2-norbornyl, n=0) wassubstituted for tricyclo[3.3.1.1^(3,7)]-decan-1-amine, and 5 moles oftriethylamine were used instead of 3 moles. M.p. 205-206° C. (ethanol).Anal. Calcd. For C₁₄H₂₅N₃O₄S₂: C, 46.26; H, 6.93; N, 11.56; S, 17.64.Found: C, 46.21; H, 6.94; N, 11.54; S, 17.63.

EXAMPLE 4

[0023]N,N¹-Bis[2-(tricyclo[3.3.1.1^(3,7)]-dec-1-yl)ethyl]imidodisulfamide (3;R=1-adamantyl, n=2)

[0024] The compound of the example was prepared by a procedure similarto that described in Example 1 except that[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]amine (1; R=1-adamantyl, n=2)was substituted for tricyclo[3.3.1.1^(3,7)]-decan-1-amine.

[0025] M.p. 162-164° C. (ethanol).

[0026] Anal. Calcd. For C₂₄H₄₁N₃O₄S₂: C, 57.68; H, 8.27; N, 8.41; S,12.83. Found: C, 57.54; H, 8.30; N, 8.32; S, 12.84.

EXAMPLE 5

[0027] N,N¹ -Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl)imidodisulfamide(3; R=1-adamantyl, n=1)

[0028] The compound of this example was prepared by a procedure similarto that described in Example 1 except that[(tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]amine (1; R=1-adamantyl, n=1)was substituted for tricyclo[3.3.1.1^(3,7)]-decan-1-amine.

[0029] M.p. 187-190° C. (ethanol). Anal. Calcd. For C₂₂H₃₇N₃O₄S₂: C,56.02; H, 7.91; N, 8.91; S, 13.59. Found: C, 55.74; H, 8.25; N, 8.83; S,13.25.

EXAMPLE 6

[0030]N,N¹-Bis[2-(tricyclo[3.3.1.1^(3,7)]dec-2-yl)ethyl]imidodisulfamide (3;R=2-adamantyl, n=2)

[0031] The compound of this example was prepared by a procedure similarto that described in Example 1 except that[2-(tricyclo[3.3.1.1^(3,7)]des-2-yl)ethyl]amine (1; R=2-adamantyl, n=2)was substituted for tricyclo[3.3.1.1^(3,7)]-decan-1-amine. M.p. 180-181°C. (ethanol). Anal. Calcd. For C₂₄H₄₁N₃O₄S₂: C, 57.68; H, 8.27; N, 8.41;S, go; 12.83. Found: C, 57.79; H, 8.66; N, 8.40; S, 12.80.

EXAMPLE 7

[0032]N,N¹-Bis[2-[(tricyclo[3.3.1.1]dec-2-ylidene)ethyl]imidodisulfamide (11)

[0033] The compound of this example was prepared by a procedure similarto that described in Example 1 except that2-(tricyclo[3.3.1.1^(3,7)]dec-2-ylidene)ethanamine (4) was substitutedfor tricyclo[3.3.1.1^(3,7)]decan-1-amine. M.p. 182-183° C. (ethanol).

[0034] Anal. Calcd. For C₂₄H₃₇N₃O₄S₂: C, 58.15; H, 7.52; N, 8.48; S,12.94. Found: C, 58.30; H, 7.58; N, 8.48; S, 12.75.

EXAMPLE 8

[0035] N,N¹-Di (tricyclo [3.3.1.1^(3,7)]dec-2-yl)imidodisulfamide (3;R=2-adamantyl, n=0)

[0036] The compound of this example was prepared by a procedure similarto that described in Example 1 except thattricyclo[3.3.1.1^(3,7)]decan-2-amine (1; R=2-adamantyl, n=0) wassubstituted for tricyclo[3.3 1.1^(3,7)]decan-1-amine and 5 moles oftriethylamine were used instead of 3 moles.

[0037] M.p. 221-222° C. (decomp.) (2-propanol).

[0038] Anal. Calcd. For C₂₀H₃₃N₃O₄S₂: C, 54.15; H. 7.50; N, 9.47; S,14.45. Found: C, 54.62; H, 7.74; N, 9.50; S, 14.06.

EXAMPLE 9

[0039] N,N¹-Dicyclooctylimidodisulfamide (3; R=cyclooctyl, n=0)

[0040] The compound of the example was prepared by a procedure similarto that described in Example 1 except that cyclooctylamine (1;R=cyclooctyl, n=0) was substituted fortricyclo[3.3.1.1^(3,7)]decan-1-amine. M.p. 183-185° C. (ethanol).

[0041] Anal. Calcd. for C₁₆H₃₃N₃O₄S₂: C, 48.58; H, 8.41; N, 10.62; S,16.21. Found: C, 48.77; H, 8.78; N, 10.54; S, 15.86.

EXAMPLE 10

[0042] N,N¹-Dicyclododecylimidodisulfamide (3; R=cyclododecyl, n=0)

[0043] The compound of this example was prepared by a procedure similarto that described in Example 1 except that cyclododecylamine (1;R=cyclododecyl, n=0) was substituted fortricyclo[3.3.1.1^(3,7)]decan-1-amine. M.p. 205° C. (ethanol).

[0044] Anal. Calcd. For C₂₄H₄₉N₃O₄S₂: C, 56.77; H, 9.73; N, 8.28; S,12.63. Found: C, 56.62; H, 9.60; N, 8.28; S, 12.26.

EXAMPLE 11

[0045] Sodium N,N¹(tricyclo[3.3.1.1^(3,7)dec-1-yl)imidodisulfamide (1;R=1-adamantyl, n=0, R¹=sodium)

[0046] N,N¹-Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide (200mg) was suspended in 5 mL of absolute methanol. Then, 1.5 mL of 10percent aqueous sodium hydroxide solution was added and the reactionmixture was heated slightly in water bath until complete dissolution ofthe imidodisulfamide 3 (R=1-adamantyl, n=0). After cooling, theresulting sodium salt precipitated as white fluffy crystalline mass. Thesolvent was stripped under vacuum leaving 200 mg of the sodium salt of 1(R=1-adamantyl, n=0, R¹=sodium). M.p. over 200° C. (water).

EXAMPLE 12

[0047] N,N¹(tricyclo[3.3.1.1^(3,7)dec-1-yl) imidodisulfamideMonophosphate (1; R=1-adamantyl, n=0, R¹=P(O) (OH)₂)

[0048] N,N -Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide (200mg; 36 mmol) and 51 mg of phosphoric anhydride (P₄O₁₀; 18 mmol) wereheated in trichloromethane (10 mL; distilled from phosphoric anhydride)overnight. After evaporation of the solvent, the residue was saturatedrepeatedly with diethyl ether until the reaction product was obtained aspowder. M.p. over 200° C.

Antiviral Activity

[0049] The antiviral activity of the compounds of the invention wasdetermined by several methods through the National Institute of Allergyand Infectious Diseases, NIH Testing Program.

[0050] According to the method of Sidwell et al. Appl. Microbiol. 22:747-801, antiviral activity is determined by using viral cytopathogeniceffect (CPE) inhibition in 96-well microplates. Seven concentrations(1,000, 320, 100, 32, 10, 3.2, and 1.0 microgram/mL final concentrationin panel cups) of compounds were employed. Compound was added to thecells to be infected 15 minutes before virus exposure. A virus dosageequivalent to the CCID50 was then administered. (The virus concentrationwhich causes 50% cell death, established by titration of a cellmonolayer with a homogenate of cultures from 100 virally infectedcells). Antiviral activity may be expressed as virus rating (VR) inaccordance with Sidwell et al., and as a minimum inhibitoryconcentration (MIC). Cytotoxicity of each dosage level of compound wasevaluated in the same plate using microscopically visible cell anomaliesas criterion for evaluation. Included with each test was a knownpositive compound—ribavirin, sodofovir (HPMPC) and/or cyclic HPMFC maybe used as positive controls for RNA viruses. The antiviral test wasread approximately 72 hours after addition of virus, at the time whenviral CPE reached essentially maximal levels.

[0051] In the plaque reduction assay using cowpox virus in cell culture,the compounds of the invention were applied both during and after virusadsorption in order to determine whether compounds were acting asinhibitors of virus adsorption as opposed to an intracellular mode ofaction. Confluent 6-well plates of monkey(Vero) cells were used. Forcompound being present during the virus adsorption process, cell mediumwas aspirated and 2× compound was applied followed by virus diluted togive about 100 plaque forming units (PFU) per well. Compound and viruscontaining medium were each in a volume of 0.2 mL. Plates were rockedevery 5-10 minutes for an hour, after which time the medium was removedand 2.0 mL of 1× compound in MEM/2% Fetal Bovine Serum was applied forthree days. For compound being present after the virus adsorptionperiod, 100 PFU of virus per 0.4 mL was rocked on cells for an hour asdescribed above. After that time, the medium was removed and 2.0 mL of1× compound in MEM/2% fetal Bovine Serum was applied per well for threedays. Wells were aspirated and covered with about 1.0 mL/well of 0.1%crystal violet in 10% buffered formalin for 5 minutes. Then, plates wereaspirated, rinsed under tap water, and blotted dry. A light box was usedto aid in counting the plaques in each well. Sidofovir (HPMPC) andcyclic HPMPC were used as positive controls.

[0052] In the cytopathic effect inhibition assay, low passage (3-10)human foreskin fibroblast (HFF) cells are trypsinized, counted, andseeded into 96-well tissue culture plates at a cell concentration of2.5×10⁴ cells in 0.1 mL of minimal essential medium (MEM) supplementedwith 10% fetal bovine serum (FBS). The cells are then incubated for 24hours at 37° C. in a 5% CO₂:95% air, 90% humidified atmosphere. Themedia is then removed and 100 microliter of MEM containing 2% FBS isadded to all but the first row. In the first row, 125 microliter ofmedia containing the compound is added in triplicate wells. Media aloneis added to both cell and virus control wells. The compound in the firstrow of wells is then diluted serially 1:5 throughout the remaining wellsby transferring 25 microliter using the Cetus Liquid Handling Machine.The plates are then incubated for 60 minutes and 100 microliter of anappropriate virus concentration added to each well, excluding cellcontrol wells, which received 100 microliter of MEM. In initialexperiments, the virus concentration utilized will be 1,000 PlaqueForming Units (PFU) per well. The plates are then incubated at 37° C. ina CO₂ incubator for five days. After the incubation period, media isaspirated and the cells stained with a 0.1% crystal violet solution forfour days. The stain is then removed and the plates rinsed using tapwater until all excess stain is removed. The plates are allowed to dryfor 24 hours, and the amount of CPE in each row determined using aBioTek Multiplate Autoreader. EC50 and IC50 values are determined bycomparing compound-treated and compound-untreated cells using a computerprogram. (The EC50 value measures compound concentration that inhibitsviral replication by 50%; the IC50 value detects compound toxicity todividing cells by measuring compound concentration that inhibits cellgrowth by 50%).

[0053] In the plaque reduction assay, two days prior to use, HFF cellsare plated into six well plates and incubated at 37° C. with 5% CO₂ and90% humidity. On the date of the assay, the compound is made up at 2×the desired concentration in 2×MEM with 5% FBS and then serially diluted1:5 using six concentrations of compound. The initial concentration is200 microgram/mL. The compound dilutions are then placed in a 42° C.water bath. The 4% agarose for the overlay is prepared with reagentquality water and microwaved until athe agarose has dissolved. This isthen placed into the 42° C. water bath to cool. The virus to be used isdiluted in MEM containing 10% FBS to a desired concentration, which willgive 20-30 plaques per well. The media is then aspirated from the wellsand 0.2 microliter of virus is added to each well in triplicate with 0.2microliter of media being added to compound toxicity wells. The platesare then incubated for one hour with shaking every 15 minutes. Afterincubation, an equal amount of agarose is added to each compounddilution. Each agarose/compound dilution is then added to theappropriate wells. The assay is incubated for five days, after which thecells are stained with 2.0 microliter per well of 5% neutral red stainfor six hours. The stain is then aspirated, and the plaques countedusing a stereomicroscope at 10× magnification.

[0054] In the cowpox virus plaque assay, in one condition the compoundof Example 1 was added to cells 5 minutes before virus adsorption andthen continuously for 3 days. In the second condition, virus wasadsorbed first for 1 hour, then the compound was added for three days.The compound of Example 1 was found to be equally active under bothconditions with an EC50 value in monkey (Vero) cells of 2.0microgram/mL. At 3.0 microgram/mL, the plaques were nearly completelyeliminated, and at 1.0 microgram/mL the plaques were tiny relative tothe untreated ones. Cell monolayers were healthy up to 30 microgram/mL(the highest concentration tested). From previous data, sidofovir(HPMPC) is active in these cells at about 12.0 microgram microgram/mL.

[0055] In the CPE inhibition assay, the compound of Example 1 showed thefollowing values measuring anti-orthopoxvirus activities: (A) vacciniavirus (HFF cells) EC50: 0.05 microgram/mL; EC90: 1.40 microgram/mL;CC50: 77.80 microgram/mL; DV50: 2.20 microgram/mL; SI: 1,556 (B) cowpoxvirus (HFF cells) EC50: 1.10 microgram/mL; EC90: 7.30 microgram/mL;CC50: 77.80 microgram/mL; CDV50: 3.80 microgram/mL; CDV90: 13.30microgram/mL; SI: 77.8

[0056] (CC50 measures the cytotoxic concentration in uninfected cells;The Selectivity Index (SI) measures the compound toxicity and iscalculated according to CC50/EC50).

[0057] In the plaque reduction assay, the compound of Example 1 showedthe following values measuring anti-orthopoxvirus activities: (A)vaccinia virus (HFF cells) EC50: 0.09 microgram/mL; EC90: 0.15microgram/mL; CC50: 100.00 microgram/mL; CDV50: 50.90 microgram/mL;CDV90: 19.9 microgram/mL; SI: 1,111 (B) cowpox virus (HFF cells) EC50:0.49 microgram/mL; EC90: 11.70 microgram/mL; CC50: 100.0 microgram/mL;CDV50: 11.70 microgram/mL; CDV90: 18.7 microgram/mL SI: 204

[0058] When tested in the CPE assay against nine variola virus(smallpox) isolates (eight major, and one minor), the compound ofExample 1 showed an average EC50 of 0.10 microgram/mL, and CC50 of 43.0microgram/mL.

[0059] In the Neutral Red Uptake Assay (using stationary HFF cells), thecompound of Example 1 showed the following values measuring toxicity:CC50: 78.9 microgram/mL; ACV CC50: over 100 microgram/mL;

[0060] In the CPE inhibition assay, the compound of Example 11 showedthe following values measuring anti-orthopoxvirus activities: (A)vaccinia virus (HFF cells) EC50: 0.04 microgram/mL; E090: 0.11microgram/mL CC50: 65.00 microgram/mL; CDV EC50: 1.80 microgram/mL; CDVFC90: 3.7 microgram/mL SI: 1,625 (B) cowpox virus (HFF cells) EC50: 0.50microgram/mL; EC90: 2.10 microgram/mL CC50: 65.00 microgram/mL; CDVEC50: 2.30 microgram/mL CDV EC90: 3.90 microgram/mL SI: 130

[0061] (CC50 measures the cytotoxic concentration in uninfected cells;The Selectivity Index (SI) measures compound toxicity and is calculatedaccording to CC50/EC50).

[0062] In the plaque reduction assay, the compound of Example 11 showedthe following values measuring anti-orthopoxvirus activities: (A)vaccinia virus (HFF cells) CC50: 87.60 microgram/mL

[0063] In the Neutral Red Uptake Assay (using stationary HFF cells), thecompound of Example 11 showed the following values measuring toxicity:CC50: 87.6 microgram/mL; ACV CC50: over 100 microgram/mL; CDV CC50: over100 microgram/mL

[0064] When tested against cowpox infection in female BALB/c mice, anintraperitoneal dose of 100 mg/kg daily of the compound of Example 11given twice daily for 5 days starting 4 hours before virus challengesignificantly reduced the virus titer on Day 3 of measurement asfollows: Lung titer on Day 3: 6.6 ± 1.3 (P < 0.05) Saline: 3.0 ± 0.2

[0065] For pharmaceutical purposes, the compounds of this invention canbe administered to warm-blooded animals perorally, parenterally,topically or intranasally as active ingredients in customary dosage unitcompositions. These dosage unit compositions contain the activeingredient and at least one inert pharmaceutical carrier. Dosage unitforms contemplated by the present invention include tablets, capsules,solutions, suspensions, aerosols, and parenteral compositions such asintramuscular, intravenous or intradermal preparations. Sustainedrelease dosage forms are also contemplated where the active ingredientis bound to an exchange resin that, optionally, can be coated with adiffusion barrier coating to modify the release properties of the resin.

[0066] The quantity of active ingredient administered in such dosageforms can vary over a wide range depending upon the mode ofadministration, the size and weight of the patient and whether thenature of the treatment is prophylactic or therapeutic in nature. Ingeneral, dosage unit forms containing from about 1.0 mg to 250 mg of theactive ingredient. In humans, the dose is administered from 1 to 4 timesdaily. The total daily dosage will be from about 5.0 mg to 1,000 mg,although lower or higher amounts can be used. A preferred total dailydose would be from 10 mg to 100 mg of active ingredient.

[0067] Pharmaceutical carriers or excipients used in the preparation ofpharmaceutical compositions for use in the invention may be eitherorganic or inorganic, solid or liquid in nature. Suitable solidexcipients include gelatin, microcrystalline cellulose, lactose,starches, and magnesium sulfate. Suitable liquid excipients includewater and alcohols such as ethanol, benzyl alcohol and polyethyleneglycols. The preferred liquid excipients for injectable preparationsinclude water, saline solution, dextrose solution and glycol solutionssuch as aqueous propylene glycol or aqueous polyethylene glycol. Theproperties of the formulations may be enhanced by the addition of one ormore adjuvants possessing properties as viscosity enhancers, surfactans,pH modifiers, preservatives, sweeteners, stability enhancers, coloringagents, suspending agents, granulating agents, coating agents,desintegration modifiers, propellants, emulsifying agents andhumectants.

[0068] The compounds of this invention may be utilized in the form ofalkali metal salts. Such salts may be formed by treating the compoundswith aqueous alkaline hydroxide solution such as but not limited tosodium hydroxide and potassium hydroxide.

[0069] The compounds of this invention may also be utilized in the formof N-substituted monophosphates. Such derivatives may be formed bytreating the compounds 1 with phosphorylating agent such as but notlimited to phosphoryl oxychloride, phosphorus trichloride.

[0070] The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof and,accordingly, reference should be made to te appended claims, rather thanto the foregoing specifications, as indicating the scope of theinvention.

1. A compound having a formula [R—(CH₂)_(n)NHSO₂]₂NR¹   (I) wherein n is0, 1 or 2, and R is a carbocyclic radical selected from the groupconsisting of adamantyl, norbornyl, cyclooctyl and cyclooctyl, and R¹ ishydrogen, alkali metal such as a sodium, potassium, etc., ammonium, anda monophosphate moiety. 2.N,N¹-Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide, a compoundaccording to claim
 1. 3.exo-N,N¹-Bis(bicyclo[2.2.1]hept-2-yl)imidodisulfamide, a compoundaccording to claim
 1. 4.endo-N,N¹-Bis(bicyclo[2.2.1]hept-2-yl)imidodisul-famide, a compoundaccording to claim
 1. 5.N,N¹-Bis[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]imidodisulfamide, acompound according to claim
 1. 6.N,N¹-Bis[(tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]imidodisulfamide, acompound according to claim
 1. 7.N,N¹-Bis[2-(tricyclo[3.3.1.1^(3,7)]dec-2-yl)ethyl]imidodisulfamide, acompound according to claim
 1. 8.N,N¹-Bis[2-(tricyclo[3.3.1.1^(3,7)]dec-2-ylidene)ethyl]imidodisulfamide,a compound according to claim
 1. 9. N,N¹-Di(tricyclo[3.3.1.1^(3,7),]dec-2-yl)imidodisulfamide, a compound according to claim
 1. 10.N,N¹-Dicyclooctylimidodisulfamide, a compound according to claim
 1. 11.N,N¹-Dicyclododecylimidodisulfamide, a compound according to claim 1.12. N,N¹-Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide sodiumsalt (R¹=Na), a compound according to claim
 1. 13.N,N¹-Bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide monophosphate[R¹=P(O) (OH) ₂], a compound according to claim
 1. 14. A method fortreating a warm-blooded animal for infections caused by orthopoxviruses,which comprises administering to such animal an effective amount of acompound according to claim
 1. 15. A method according to claim 32wherein the compound isN,N¹-bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide.
 16. A methodaccording to claim 32 wherein the compound isexo-N,N¹-bis(bicyclo[2.2.1]hept-2-yl)imidodisulfamide.
 17. A methodaccording to claim 32 wherein the compound isendo-N,N¹-bis(bicyclo[2.2.1]hept-2-yl) imidodisulfamide.
 18. A methodaccording to claim 32 wherein the compound isN,N¹-bis[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]imidodisulfamide. 19.A method according to claim 32 wherein the compound isN,N¹-bis[(tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]imidodisulfamide.
 20. Amethod according to claim 32 wherein the compound isN,N¹-bis[2-(tricyclo[3.3.1.1^(3,7)]dec-2-yl)ethyl]imidodisulfamide. 21.A method according to claim 32 wherein the compound isN,N¹-bis[2-(tricyclo[3.3.1.1^(3,7)]dec-2-ylidene)ethyl]imidodisulfamide.22. A method according to claim 32 wherein the compound isN,N¹-di(tricyclo[3.3.1.1^(3,7)]dec-2-yl)imidodisulfamide.
 23. A methodaccording to claim 32 wherein the compound isN,N¹-dicyclooctylimidodisulfamide.
 24. A method according to claim 32wherein the compound is N,N¹-dicyclododecylimidodisulfamide.
 25. Amethod according to claim 32 wherein the compound isN,N¹-bis(tricyclo[3.3.1.1^(3,7)]dec-1-yl)imidodisulfamide sodium salt(R¹=Na).
 26. A process for preparing a compound of the formula[R—(CH₂)_(n)NHSO₂]₂NH comprising reacting a compound of the formulaR—(CH₂)_(N)NH₂ with HN(SO₂Cl)₂ in the presence of triethylamine, whereinn is 0, 1 or 2, and R is a carbocyclic radical selected from the groupconsisting of adamantyl, norbornyl, cyclooctyl and cyclododecyl.
 27. Aprocess for preparing a compound of the formula [R—(CH₂)_(n)NHSO₂]₂N⁻Me⁺ comprising reacting a compound of the formula [R—(CH₂)_(n)NHSO₂]₂NHwith aqueous alkaline hydroxide solution such as but not limited tosodium hydroxide and potassium hydroxide, wherein n is 0, 1 or 2, R is acarbocyclic radical selected from the group consisting of adamantyl,norbornyl, cyclooctyl and cyclododecyl, and Me is alkaline metal such assodium and potassium.
 28. A process for preparing a compound of theformula [R—(CH₂)_(N)NHSO₂]₂N—P(O) (OH)₂ comprising reacting a compoundof the formula [R—(CH₂)_(n)NHSO₂]₂NH with a phosphorylating agent suchas but not limited to phosphoric anhydride, phosphorous trichloride,phosphorous pentoxide and phosphorous oxychloride in organic solventsuch as but not limited to trichloromethane, toluene, and benzene,wherein n is 0, 1 or 2, and R is a carbocyclic radical selected from thegroup consisting of adamantyl, norbornyl, cyclooctyl and cyclododecyl.